Controlled release pharmaceutical composition

ABSTRACT

A sustained/prolonged release pharmaceutical dosage form is disclosed. The form comprises a hard shell capsule and a formulation comprising (a) a water insoluble medicament, (b) a high melting fatty ester, (c) a low viscosity oil, (d) a cellulosic polymer, and (e) a non-ionic surfactant.

BACKGROUND OF THE INVENTION

[0001] One of the most frequently utilized methods to extend theduration of drug action in the body is by modification of thepharmaceutical dosage form. This is usually achieved with single ormulticomponent matrix systems such as granules, pellets, tablets or acombination of the above where the drug delivery is mainly controlled bydiffusion or erosion mechanisms.

[0002] Another commonly used procedure to sustain or control the rate ofdrug release is by utilizing polymer coating technology. Polymers withpH dependent or independent properties are coated onto the differentdosage forms utilizing fluid bed or conventional coating equipment.

[0003] The delivery systems described above, traditionally have beenused to manufacture many of the available pharmaceutical dosage forms inthe market. However, for drugs that present a low melting point or aremetastable at room temperature the only available solid oral unit dosageform has been the soft gelatin capsule.

[0004] Soft gelatin encapsulation is rather a complex process andusually requires the services of an outside contractor. However, manypharmaceutical companies would prefer to keep development activitiesin-house for reasons of confidentiality and control over the developmentprocess. With the new advances in pharmaceutical equipment technology itis now possible to formulate drug substances into semi-solid, liquid orpaste-like form for filling into hard-shell two piece capsules. Thistype of formulation technology demonstrates an alternative for thedifficult to manufacture soft gelatin technology and the ability tomaintain the development activities in-house.

[0005] There are several advantages that can be obtained by formulatingdrugs in liquids and/or semisolid (molten) formulations to be filledinto hard shell two piece capsules. These are the ability to formulatewith low melting point materials, low-dosed or highly potent drugs,compounds that are oxygen- or moisture sensitive, and for drugs thatrequire bioavailability enhancement.

[0006] Many of the liquid formulations in hard-shell capsules provide animmediate or fast release. This is usually achieved as a result of theimmediate release of the contents due to the fast disintegration time ofthe gelatin at body temperature. Other formulations utilize sustainedrelease liquid-filled release capsules utilizing thermosofteningmatrices. The excipients most frequently utilized are the Gelucires®,Gattefosse®, France, since they are available as semisolids with a widerange of melting points and HLB values. This variety allows flexibilityin mixing, adequate filling viscosity, different degrees ofbioavailability enhancement and a sustained drug release from thesemisolid matrix.

[0007] High melting glycerides have frequently been used as lubricantswhen formulating tablets or capsules. Lubricants have a great effect onthe aspect of the finished product and the ejection of the tablet out ofthe die is improved. Lubricants are usually hydrophobic substances andwhen used in high amount can alter the desegregation time of the tabletthus delaying the bioavailability of the active ingredient.

[0008] The incorporation of lubricants (waxes, HMG) into tablet matriceshas been a popular method to prolong drug release. For example,sustained release acetaminophen tablets with glyceryl behenate, KlucelHXF, hydroxy propyl cellulose (HPC), a swellable water-soluble polymer,and Carbopol® 934, a crosslinked polymer, has been prepared. It wasobserved that all tablets containing a sustained release agent exhibitedsome degree of prolonged drug release in vivo as compared to regulartablets. It was also noted that from all sustained release agentsevaluated, glyceryl behenate provided the slowest release.

[0009] Glyceryl behenate as a potential controlled release wax matrix inspheres and tablets has been evaluated (10, 30 and 50%). At the 10%level no sustained action was observed. However, as the levels ofglyceryl behenate increased a significant slower release of the drug wasobtained. The results indicated that glyceryl behenate exhibited thepotential to create a controlled release matrix.

[0010] Sustained release preparations have also been achieved from otherhigh melting glycerides (glycerol palmitostearate and glycerylmonostearate). For example the release of theophylline embedded in aglycerol palmitostearate matrix containing varying amounts of mannitoland/or hydroxypropyl methyl cellulose 4000 (HPMC) was evaluated. Therelease of theophylline was modulated by varying the fraction of HPMCand/or mannitol used. When both HPMC and mannitol were used the matrixsystem developed followed a first-order dissolution release.

[0011] In general, natural, synthetic and/or semi-synthetic polymerssuch as cellulose or acrylics derivatives, have been used in highquantities (>10%) to retard the release of many pharmaceutical activeingredients. Such polymers are not usually recommended to be utilized insmall quantities to retard the release of API.

SUMMARY OF THE INVENTION

[0012] A controlled release pharmaceutical formulation is disclosed. Theformulation comprises a matrix construct of a component selected from ahigh melting point fatty acid ester, an oil, a polymeric cellulosederivative, and a mixture of any of the foregoing, having a selectedmedicament associated therewith.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The accompanying drawing illustrates the invention. In such adrawing:

[0014]FIG. 1 is a graphical representation of the in vitro release oflovastatin using Compritol 888;

[0015]FIG. 2 is a graphical representation of the in vitro release oflovastatin using Precirol ATO5;

[0016]FIG. 3 is a graphical representation of the in vitro release ofhydroxyzine pamoate using low HLB sufactant;

[0017]FIG. 4 is a graphical representation of the in vitro release ofhydroxyzine pamoate using high HLB surfactant; and

[0018]FIGS. 5 and 6 are graphical representations of the dissolutionprofiles of nifedipine.

DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention relates to a sustained or modulatedpharmaceutical formulation comprising (1) a selected water insolublemedicament or drug, (2) a suitable construct with which the drug isassociated, i.e. is encapsulated therewithin or being part of theconstruct. The construct provides a modulated release of the associated,e.g. encapsulated, drug to the body of a patient, e.g. a human being oranother animal, when the construct is administered e.g. orally, to thepatient.

[0020] As used herein the term “a water insoluble medicament, drug oractive ingredient” includes such medicament drug or active ingredientthat is (1) a sparingly soluble in water, i.e. 1 part solute into about30 to about up to about 100 parts of water; (2) “slightly watersoluble”, i.e. 1 part of solute into about 100 to up to about 1,000parts of water; (3) “a very slightly water soluble”, i.e. 1 part ofsolute into about 1000 to up to about 10,000 parts of water; and (4)“practically water insoluble”, i.e. 1 part of solute to at least about10,000 parts of water; as defined in USP XXII.

[0021] The formulation is intended to be administered orally to thepatient in a dosage form comprising a hard shell capsule filled with theformulation.

[0022] Suitable therapeutic medicament categories of drugs ormedicaments are those which are water insoluble and includecardiovascular drugs, antiallergics, analgesics, bronchodilators,antihistamines, antitussives, antifungals, antivirals, antibiotics,other pain medicaments, antiinflamatories, etc. Particularly suitablemedicaments include hydroxyzine pamoate; dihydropyridine calcium channelblockers, e.g. nifedipine, nimodipine, nisoldipine, nicardipine,amoldipine, etc.; statins e.g. atorvastatin, simvastatin, lovastatin,etc., anticonvulsants, e.g. phenytoin, carbamezepine, etc.; analgesics,e.g. ibuprofen, naproxen, indomethacin, etc. steroids, e.g. prednisone,prednisolone, hydrocortisone, etc.; fibrates, e.g. gemfibrozil,fenofibrate, clofibrate, etc.; vitamins, e.g. vitamins A, D, E and K,etc.

[0023] For purposes of the formulations of this invention, which areintended for incorporation into a hard shell capsule unit dosage form,the biotherapeutic medicament or drug is associated with the constructcarrier with which it is destined to be combined. By “associate” or“associated” is meant that the water insoluble medicament is present asa matrix or a part of the matrix along with the component making up theconstruct or is encapsulated within the carrier matrix, or is on thesurface of the carrier matrix.

[0024] A suitable construct is selected. Such a construct is one whichwill incorporate or encapsulate the selected medicament and provide acontrolled or modulated release of the medicament therefrom to the sitesof action or application to the patient's body, e.g. to thehepatobiliary receptors of the human being or other animal.

[0025] A suitable carrier construct comprises a material or componentselected from the group comprising a high melting fatty acid ester, suchas for example glyceryl behenate, gyceryl palmitosterate andglycerylstearate; low viscocity oils, e.g. vegetable oils, hydrogenatedvegetable oils, corn oil, cottonseed oil, menhaden oil, safflower oil,sesame oil, shark-liver oil, soybean oil, olive oil and wheat germ oil;saturated, polyglycolyzed, glycerides, a cellulosic polymer, e.g.methocel E series, methocel A series, methocel K, series ethocel Pseries, low-substituted hydroxypropyl ether cellulose polymers, L Hseries methocel and a mixture of any of the foregoing.

[0026] A most preferred cellulosic polymer is a methylcellulose polymerhaving a structure,

[0027] which are commercially available from the Dow Chemical Company,Midland, Mich., under the tradename“METHOCEL”. e.g. METHOCEL A. Anothermost preferred cellulosic polymer is a hydroxypropoxyl methyl cellulosepolymer having a structure,

[0028] which are commercially available (Dow Chemical Company) under thedesignations METHOCEL E, METHOCEL F, METHOCEL and METHOCEL K brandproducts. Preferably, the formulation comprises a mixture of at leasttwo of the foregoing components.

[0029] The dosage form comprising a hard shell capsule utilizes theformulation, i.e. the construct or the matrix having the medicamentassociated therewith. Preferably, the sustained/prolonged releasepharmaceutical unit dosage form comprises the matrix or constructformulated from a mixture of the above-described materials orcomponents.

[0030] The high melting fatty acid esters (high melting glycerides) ofthe formulation and the sustained/prolonged release capsule unit dosageforms of the present invention comprise esters of fatty acids andpolyhydric alcohols, such as glycerol, melting at elevated temperatureswithin the range of from about 50° to about 80° C. The melting points offatty acid esters of behenic acid (docosanoic acid), palmitostearic acidand stearic acid and glycerol fall within this range and are suitablefor the formulations and unit dosage forms of the present invention.Other high melting fatty acid esters, that is, fatty acid esters meltingwithin the range (about 50° to about 80° C.), may be employed in theformulations and dosage forms.

[0031] The oils of the formulations and the sustained/prolonged releasecapsule unit dosage forms of the present invention comprisetriglycerides of fatty acids having short (12 to 14 carbon atoms),medium (16 to 18 carbon atoms) and long (18 to 22 carbon atoms) carbonchains and no, or up to 6 double bonds. Exemplary fatty acids are lauricacid (12 carbon atoms, no double bonds), myristic acid (14 carbon atoms,no double bonds), palmitic acid (16 carbon atoms, no double bonds),palmitoleic acid (16 carbon atoms, one double bond), stearic acid (18carbon atoms, no double bonds), oleic acid (18 carbon atoms, 1 doublebond), linoleic acid (18 carbon atoms, 2 double bonds), eicosapentaenoicacid (20 carbon atoms, 5 double bonds (“EPA”) and docosahexanoic acid(22 carbon atoms, 6 double bonds), which are found in various animal andvegetable oils listed in the Table below. TABLE Super Refined ® Oils andthe Associated Typical Fatty Acid Distribution (%) Super Refined ProductMyristic Palmitic Palmitoleic Stearic Oleic Linoleic Linolenic EPA DHACorn 1 10 0 3 30 55 0 0 0 Cotton- 1 24.5 0 2.5 17 55 <1 0 0 seedMenhaden 8.5 23 12.5 3 12.5 2 <1 12 8.5 Olive 0 11.5 1 2 75 9.5 0 0 0Peanut 0 7.5 1 4.5 62 20 0 0 0 Safflower 0 7 0 3 15 75 0 0 0 Sesame 0 80 4.5 43 41 0 0 0 Shark-liver 2 12 7 4 30 6 5 4 4 Soybean 0 9 0 4 24 528 0 0 Wheat- 0 13.5 0 3.5 19 54.5 7 0 0 germ

[0032] The cellulosic polymers of the formulations andsustained/prolonged release capsule unit dosage forms of the presentinvention comprise glucose polysaccharide ethers having multiple glucoseunits and methyl, ethyl, hydroxyethyl, hydroxypropyl or hydropropylmethyl substitution. Exemplary cellulosic polymers having methylethersubstitution are the Methocels, i.e., methocel E10, methocel A4M,methocel K15M, methocel K100LV and methocel K100M, and the Ethocels, forexample, ethocel P20 and low-substituted hydroxypropyl ether cellulosepolymers LH11, LH22 and LH30.

[0033] Surfactants which may optionally be employed with theformulations and sustained/prolonged release capsule unit dosage formsof the present invention, comprise polysorbates, such as ethers ofpolyoxyethylene sorbitan and fatty acids. Exemplary surfactants arepolysorbate 80 and polyoxyethylene 20 sorbitan monoleate,polyoxyxethylene alkyl ethers of the Brij- or Volpo series, CremophorRH, Cremophor EL, polyoxyethylene sorbitan fatty acid esters of theTween- or Crillet series, polyoxyethylene stearates of the Cerosynt- orMyrj series, lecithin, poloxamers, d-2-tocophenyl polyethylene glycol1000 succinate (Vitamin E TPGS) and saturated polyglycolized glycerides(Labrasol, Labrafil and Gelucires), polyoxyethylene castor oilderivations, such as polysorbate 80 which is preferred.

[0034] The release of the insoluble or partially water soluble activeingredient or drug of the pharmaceutical unit dosage forms of thepresent invention is sustained over a prolonged period of about 24hours. The sustained release of the water insoluble medicament from ahard shell capsule is dependent upon the type and amount of medicament,the high melting fatty acid ester, cellulose polymer and a surfactant(if employed).

[0035] The most preferred formulation comprises a water insolublemedicament, and a mixture comprising glyceryl behenate as the fatty acidester, an oil, a cellulosic polymer, such as for example, a methyl orethyl ether of a cellulose, e.g., a methocel or an ethocel, andpolysorbate 80 surfactant.

[0036] Optionally, pharmaceutically acceptable excipients, compatiblewith the requirements for filling the capsules that the formulation bein the fluid state, i.e., a liquid or semi solid, at the fillingtemperature, may be included in the formulation. Such excipientscomprise a surfactant, such as for example polysorbate 80;stabilizers/antioxidants, such as for example butylated hydroxytoluene,propyl gallate, vitamin E, ascorbic acid and ethylene diaminetetraacetic acid; solubilizers, such as for exampleN-methyl-2-pyrrolidone, citrate esters, e.g., Citroflex 2, acetylatedmonoglycerides, e.g., Triacetin and Mygliols; viscosity modifiers, suchas for example polyethylene glycols, e.g. PEG, and silica derivatives,e.g., silicon dioxide; and fillers such as for example hydrocarbons,e.g., paraffin and mineral oil. Preferably, combined with the componentor components of the carrier and the drug is a surfactant, such aspolysorbate 80.

[0037] The release of water insoluble medicaments from the unit dosageformulation generally depends on the type and amount of the high meltingfatty acid in the formulation and varies substantially with the type andamount thereof. For example, the release of lovastatin from aformulation containing the same cellulose (methocel) component over aprolonged period of about 24 hours, is fastest with Precirol AtO5,slowest with Compritol 888. The release of Lovastatin/Ethocel from aformulation of the precirol is moderately faster as the same formulacontaining compritol and ethocel.

[0038] The release of water insoluble medicament from a unit dosageformulation is markedly dependent on the type and amount of thecellulosic polymer. For example, lovastatin, compritol, is releasedconsiderably faster from a formulation of Methocel K100M than EthocelP20. Similarly, lovastatin/precirol is released from a unit dosageformulation faster when the formulation contains Methocel K100M thanEthocel P20.

[0039] The formulations of the water insoluble medicaments of thepresent invention are useful for encapsulation in hard shell capsulesfor oral administration for the treatment of various diseases anddisorders, for example, lovastatin, as an antilipidimic, or nifedipineas an antihypertensive agent, hydroxyzine pamoate as a antihistamine.The drugs are readily available from commercial suppliers.

[0040] The high melting fatty acid esters, the oils, the cellulosicpolymers and surfactants and other excipients of the formulations of thepresent invention suitable for encapsulation in hard shell capsules aregenerally available from commercial sources. The water insolublemedicaments are also commercially available. Pharmaceutically acceptableacids and bases required for salt formation of water insolublemedicaments are available from suppliers such as Aldrich ChemicalCompany, Milwaukee, Wis.

[0041] The sustained/prolonged release pharmaceutical unit dosage formsare prepared by fluidizing matrix carrier material or components, e.g. ahigh melting fatty acid ester, an oil, a cellulosic polymer or a mixtureof the foregoing, to provide a formulation, to which is added themedicament which dissolves therein, which is then filled into a hardshell capsule, while in the fluid state, and, generally, allowed tosolidify in the capsule. The filling of the hard shell capsule isconveniently performed by a capsule filling machine for liquid fillingof the type available, for example, from Robert Bosch GmbH, (Hofligenand Kars GKF/L Series), Germany, Harro Hoefleger GmbH, (KFM/L Series),Germany, or Zanasi Nigris SpA (AZ 20/L Series), Italy. The hard shellcapsules are generally sealed by one of several methods. The filledcapsule may be sprayed with a water alcohol mixture to seal the cap tothe body of the container. Alternatively, the cap may be sealed to thebody of the container by a bonding process, which entails passing thecap over a revolving wheel immersed in a water gelatin or a cellulosebath and then passing the capsule through a drying chamber to seal thegap between the cap and the body of the capsule with dried gelatin orcellulose. The bonding is generally performed on commercially availablemachines manufactured by Robert Bosch GmbH and Zanasi Nigris SpA, makersof capsule filling machines.

[0042] Empty hard shell capsules are commercially available from theCapsugel Division of Warner-Lambert Co., Greenwood, S.C., and fromShionogi Qualicaps, Whitsett, N.C., in various sizes to accommodate thedosage requirements for the treatment of disease or disorder states. Forexample, size 0 may be employed for unit dosage forms for potent drugformulations whereas size 000 would be required for a less potent drug,depending on the amounts of the components of the formulation andexcipients.

[0043] Gelatin and hydroxypropylmethylcellulose (HPMC) capsules may beused as containers for the formulations. Hydroxypropylmethylcellulosecapsules are preferred.

[0044] The following examples are illustrative and do not define thescope of the invention described and claimed herein.

EXAMPLES General Example

[0045] The sustained/prolonged release formulations of the presentinvention are generally prepared by heating the matrix component orcomponents until liquid (a melt), usually at the capsule fillingtemperature (70-90° C.) and adding the water insoluble medicament to themelt. The amount of water insoluble medicament utilized in allformulations is about 20% of the total amount of the formulation. Size#0 Hard-Shell hydroxypropylmethylcellulose capsules are utilized sincethey are heat resistant. In order to assure proper mixing and to reducethe amount of air entrapped with stirring (vortex created), batchescontaining a minimum of 50 grams are prepared. A general formulation isillustrated below. Ingredients % Qty (g) Medicament 20.0 10.00 HighMelting Glyceride 25.0 12.50 Surfactant 1.0 0.50 Cellulose Polymer 3.01.50 Vegetable oi 51.0 25.50 Total 100.0 50.00

Example 1

[0046] Soybean oil, polysorbate 80, and Compritol 888 in the amountsshown in Table 1 were weighed and placed in a glass beaker. The mixturewas heated to 75-80° C. until the contents melted by immersing thebeaker into a water bath heated by a Hot-Plate. The melt in the amountshown in Table 1 below was stirred with a laboratory mixer fitted with astraight blade propeller to disperse the ingredients and create anhomogeneous melt. To the melt, Methocel E or Ethocel 10P was slowlyadded with heating and stirring. After addition of the Methocel E 10Pwas complete, the melt was cooled to approximately 70° C., and thencooled at approximately 70° C., the water insoluble medicamentlovastatin, was slowly added, and the melt was stirred until uniform.Capsules size 0 were filled with 500 mg of melt, with a pipette. Thefilling weights of each capsule were recorded to guarantee consistency.The melt was all regular type maintained at approximately 70° C. duringthe filling process. The release of the medicament, lovastatin, was thendetermined.

[0047] The dissolution release of the formulations was determined by theUSP Basket Method (Apparatus 1). By this method, samples are tested in a40 mesh basket rotating at 100 RPM. Release media were used in a volumeof 900 Ml per dissolution vessel, maintained at 37° C. Double distilleddeionized water with 1% sodium dodecyl sulfate was generally used as thedissolution media. Nine samples of 3.0 ml each were automaticallycollected at 2, 4, 6, 8, 10, 12, 14, 20 and 24 hours. The absorbency ofthe samples was measured at the peak wavelength in the ultravioletspectrum with Hewllet Packard model 8453 spectrophotometer. Theabsorbency values were converted to percentages of added medicament thatwas released.

[0048]FIG. 1 shows the in vitro release of lovastatin using Compritol888 and different cellulose products in the capsule system. The Methocelproducts differ in their chemical substitution attached to its cellulosebackbone. The chemical substituents are hydroxypropoxyl and methoxylgroups. The methoxyl substituent provides more hydrophobicity and doesnot contribute to a great extent to the hydrophilic nature of thecellulose polymer thus having minimal influence on the rate of polymerhydration. On the other hand, the more hydrophilic hydroxypropoxyl groupdoes contribute greatly to the rate of polymer hydration. Consequently,Methocel K products have the fastest rate of hydration than the otherpolymers due to its higher amount of the hydroxypropoxyl groups and alower amount of the hydrophobic methoxyl group. Methocel E has a highercontent of methoxyl group than hydroxypropoxyl groups attached thusproviding a slower rate of hydration. Ethocel is a water insolublepolymer, with the same cellulose backbone and no water hydratingproperties. The polymer is only organosoluble. The results show that forall formulas evaluated a sustained release of the drug was obtained. Thefastest hydrating polymers provided a faster release thus allowingmodulation of the sustained release effect. (Methocel K>MethocelE>Ethocel). TABLE 1 Formula/ Ingredients 1 2 3 Lovastatin 20.0 20.0 20.0Compritol 888 25.0 25.0 25.0 Methocel E10P 3.0 Methocel K100M 3.0Ethocel P20 3.0 Olive Oil 51.0 51.0 51.0 Polysorbate 80 1.0 1.0 1.0

EXAMPLE 2

[0049] Following the procedure of Example 1, using the amounts of thecomponents shown in Table 2 below, hard shell capsules of theformulations were obtained. The release of the medicament was determinedby the procedure of Example 1, and the results are recorded graphicallyin FIG. 2.

[0050]FIG. 2 shows the in vitro release of lovastatin using PrecirolATO5 and different cellulose based products in the capsule system.Precirol ATO5 has a lower melting point than Compritol 888 due toshorter fatty acid chains. Compritol 888 which is glyceryl behenatecontains a 22 carbon fatty acid length chain. Precirol ATO5 is an equalmixture of the palmitate and sterate, 16 and 18 carbon unitsrespectively. The use of a lower melting glyceride resulted in fasterdissolution profiles of the water insoluble lovastatin. For systemscontaining the fast hydrating Methocel polymers, lovastatin wascompletely released in 4 hours. For systems containing the non-hydratingEthocel a sustained release of the lovastatin was obtained over 24hours. It is clearly demonstrated that the dissolution release isdependent on the type of polymer used. TABLE 2 Formula/ Ingredients 1 23 Lovastatin 20.0 20.0 20.0 Precirol ATO 5 25.0 25.0 25.0 Methocel E10 P3.0 Methocel K100M 3.0 Ethocel 3.0 Olive Oil 51.0 51.0 51.0 Polysorbate80 1.0 1.0 1.0

Example 3

[0051] This example illustrates the release of the active pharmaceuticalingredient hydroxyzine pamoate. In order to optimize the inclusion ofthis water insoluble salt in the capsule semisolid matrix, severalsurfactant classes and levels were evaluated (1-10% by weight). Atlevels lower than 2% by weight significant sample to samplevariabilities were observed in the dissolution profiles indicating thatthe matrix was not well dispersed or a non-homogeneous mixture wasobtained. Since excessive amounts of surfactant are not recommended fororal intake, the smallest amount which provides minimal sample to samplevariability was evaluated (2% by weight level). These formulationslisted in Table 3 below were prepared by melting the Compritol 888 withLabrasol and the specified surfactant in a suitable size beaker. Thetemperature of the mixture was kept at 75-80° C. with the aid of aheated plate and water bath. The mixture was constantly mixed until itbecame homogeneous. Once the mixture was homogeneous and free of anyagglomerates, the cellulose polymer was added slowly to the melt withcontinuous mixing. The temperature of the mixture was then lowered toapproximately 70° C. Once the mixture cooled to approximately 70° C.,the hydroxyzine pamoate was slowly dispersed. The final melt was mixedwell until uniform. Utilizing an appropriate pipette HPMC Capsules (#0)were filled with 500 mg of the melted mixture. The liquefied meltimmediately solidified at room temperature. The actual filling weightswere recorded for each capsule. Empty capsules were tared and balancezeroed. The melt mixture was maintained at approximately 70° C. duringthe filling operation.

[0052] The results of combinations utilizing a low HLB surfactant areshown in FIG. 3. The results utilizing a high HLB surfactant are shownin FIG. 4. TABLE 3 Formula/ Ingredients 1 2 3 4 Hydroxyzine Pamoate 20.020.0 20.0 20.0 Compritol 888 25.0 Methocel K100 3.0 3.0 Methocel E10 PEthocel 3.0 3.0 Precirol ATO 5 25.0 Labrasol 51.0 51.0 51.0 51.0Polysorbate 80 2.0 2.0 2.0 2.0

Example 4

[0053] This example further illustrates the modulated sustained releasebehavior of nifedipine. Nifedipine is a calcium channel blocking agentindicated for the management of hypertension and other cardiovasculardiseases. Extended release tablets are available at 60 and 90 mg doses.In order to adjust for the proper and recommended dosing, the filledweight of the capsules was reduced to 450 mg. At a 20% medicament leveleach capsule will contain a total of 90 mg nifedipine. The proceduresused to manufacture the capsules were the same as those described inExample 1. The formulation and the percentages for each are described inTable 4—below. The dissolution profiles demonstrating the modulatedsustained release effect of the capsule matrix and the effect of thepolymer and surfactant combinations are seen in FIGS. 5 and 6. TABLE 4Formula/ Ingredients 1 2 3 4 Nifedipine 20.0 20.0 20.0 20.0 Compritol888 25.0 Methocel K100 3.0 3.0 Methocel E10 Ethocel 3.0 3.0 Precirol ATO5 25.0 Labrasol 51.0 51.0 51.0 51.0 Polysorbate 80 2.0 2.0 2.0 2.0

We claim:
 1. A sustained/or prolonged release pharmaceutical unit dosageform comprising a hard shell capsule and a formulation comprising: (a) awater insoluble medicament; (b) a high melting fatty acid ester selectedfrom the group consisting of glyceryl behenate, glyceryl palmitostearateand glyceryl stearate; (c) a low viscocity oil selected from the groupconsisting of corn oil, cottonseed oil, menhaden oil, safflower oil,sesame oil, shark-liver oil, soybean oil, olive oil and saturatedpolyglycolized glycerides; (d) a cellulosic polymer selected from thegroup consisting of methocel A series, methocel E series, methocel Kseries, and ethocel P series; low-substituted hydroxypropyl ethercellulose polymers selected from the group consisting of LH11, LH22, andLH30; and (e) a non-ionic surfactant.
 2. A pharmaceutical unit dosageform according to claim 1 wherein the high melting fatty acid estercomprises from about 10% to about 50% by weight of the total weight ofthe formulation.
 3. A pharmaceutical unit dosage form according to claim2 wherein the high melting fatty acid ester comprises from about 15% toabout 35% by weight of the total weight of the formulation.
 4. Apharmaceutical unit dosage form according to claim 3 wherein the highmelting fatty acid ester comprises about 25% by weight of the totalweight of the formulation.
 5. A pharmaceutical unit dosage formaccording to claim 1 wherein the oil comprises about 40% to about 60% byweight of the total weight of the formulation.
 6. A pharmaceutical unitdosage form according to claim 5 wherein the oil comprises about 50% byweight of the total weight of the formulation.
 7. A pharmaceutical unitdosage form according to claim 1 wherein the cellulosic polymercomprises from about 1% to about 5% by weight of the total weight of theformulation.
 8. A pharmaceutical unit dosage form according to claim 7wherein the cellulosic polymer comprises from about 3% by weight of thetotal weight of the formulation.
 9. A pharmaceutical unit dosage formaccording to claim 1 wherein the surfactant comprises about 1.0% toabout 10% by weight of the total weight of the formulation.
 10. Apharmaceutical unit dosage form according to claim 9 wherein thesurfactant comprises from about 2% by weight of the total weight of theformulation.
 11. A pharmaceutical unit dosage form according to claim 1wherein the high melting fatty acid ester comprises from about 10% toabout 50% by weight, the oil comprises about 46% to about 61% by weight,the cellulosic polymer comprises from about 1% to about 5% by weight andthe surfactant comprises from about 1.0% to about 10% of the totalweight of the formulation.
 12. A pharmaceutical unit dosage formaccording to claim 11 wherein the higher melting fatty acid estercomprises from about 15% to about 35% by weight of the total weight ofthe formulation.
 13. A pharmaceutical unit dosage form according toclaim 12 wherein the higher melting fatty acid ester comprises about 25%by weight, the oil comprises about 51% by weight, the cellulosic polymercomprises about 3% by weight, and the surfactant comprises about 1% ofthe total weight of the formulation.
 14. A pharmaceutical unit dosageform according to claim 1 wherein the water insoluble medicamentcomprises about 20% by weight of the total weight of the formulation.15. A pharmaceutical unit dosage form according to claim 1 wherein thehigh melting fatty acid ester comprises about 10% to about 50% byweight, the oil comprises from about 46% to about 61% by weight, thecellulosic polymer comprises from about 1% to about 5% by weight, andthe surfactant comprises from about 1.0% to about 10% by weight, and thewater insoluble medicament comprises about 20% by weight of the totalweight of the formulation.
 16. A pharmaceutical unit dosage formaccording to claim 15 wherein the high melting fatty acid estercomprises about 25% by weight, the oil comprises about 51% by weight,the cellulosic polymer comprises about 3% by weight, and the surfactantcomprises about 2.0% and the water insoluble medicament comprises about20% by weight of the total weight of the formulation.
 17. Apharmaceutical unit dosage form according to claim 1 wherein said waterinsoluble medicament is a medicament selected from the group consistingof hydroxyzine pamoate, nifedipine, nimodipine, nisoldipine,nicardipine, amlodipine, atorvastatin, simvastatin and lovastatin,genfibrozil, fenofibrate and clofibrate
 18. A pharmaceutical formulationcomprising a water insoluble medicament selected from the groupconsisting of hydroxyzine pamoate, nifedipine, nimodipine, nisoldipine,nicardipine, amlodipine, atorvastatin, simvastatin, lovastatin,genfibrozil, fenofibrate and clofibrate associated with, (a) a highmelting fatty acid ester selected from the group consisting of glycerylbehenate, glyceryl palmitostearate and glyceryl stearate; (b) an oilselected from the group consisting of corn oil, cottonseed oil, menhadenoil, safflower oil, sesame oil, shark-liver oil, soybean oil, olive oil,wheat grain oil and a low viscocity polyglycolized glyceride; (c) acellulosic polymer selected from the group consisting of methocel Eseries, methocel A series, ethocel P series, methocel K series, lowsubstituted hydroxypropyl ether cellulosic polymers, selected from thegroup consisting of LH11, LH22 and LH30; and (d) a non-ionic surfactant.19. A pharmaceutical unit dosage form according to claim 18 wherein thehigher melting fatty acid ester comprises from about 10% to about 50% byweight of the total weight of the formulation.
 20. A pharmaceuticalformulation according to claim 19 wherein the high melting fatty acidester comprises from about 15% to about 35% by weight of the totalweight of the formulation.
 21. A pharmaceutical formulation according toclaim 20 wherein the high melting fatty acid ester comprises from about25% by weight of the total weight of the formulation.
 22. Apharmaceutical formulation according to claim 18 wherein the oilcomprises about 46% to about 61% by weight of the total weight of theformulation.
 23. A pharmaceutical formulation according to claim 22wherein the oil comprises about 51% by weight of the total weight of theformulation.
 24. A pharmaceutical formulation according to claim 18wherein the cellulosic polymer comprises from about 1% to about 5% byweight of the total weight of the formulation.
 25. A pharmaceuticalformulation according to claim 24 wherein the cellulosic polymercomprises from about 3% by weight of the total weight of theformulation.
 26. A pharmaceutical formulation according to claim 18wherein the high melting fatty acid ester comprises from about 10% toabout 50% by weight, the oil comprises about 46% to about 61% by weight,the cellulosic polymer comprises from about 1% to about 5% by weight andthe surfactant comprises from about 1.0% by weight of the total weightof the formulation.
 27. A pharmaceutical formulation according to claim18 wherein the high melting fatty acid ester comprises about 25% byweight, the oil comprises about 51% by weight, the cellulosic polymercomprises about 3% by weight, and the surfactant comprises from about1.0% by weight of the total weight of the formulation.
 28. A process forthe preparation of a sustained/prolonged release pharmaceutical unitdosage form comprising the steps of: (a) fluidizing a high melting fattyacid ester, (b) granulating the fluidized fatty acid ester, an oil, acellulosic polymer, a surfactant and a water insoluble medicament; (c)transferring the fluidized granulate to a hard shell capsule.
 29. Aprocess according to claim 28 wherein the water insoluble medicament isselected from the group consisting of hydroxyzine pamoate, nifedipine,nimodipine, nisoldipine, nicardipine, amoldipine, atorvastatin,simvastatin, lovastatin, genfibrozil, fenofibrate and clofibrate.
 30. Aprocess according to claim 28 wherein the high melting fatty acid esteris fluidized at a temperature in the range of about 75° to 80° C. 31.The process according to claim 28 wherein the fluidized granulate istransferred to a hard shell capsule at a temperature of about 70° C. 32.A pharmaceutical unit dosage form according to claim 1 wherein the hardshell capsule comprises hydroxypropyl methylcellulose.
 33. A processaccording to claim 28 wherein the hard shell capsule compriseshydroxypropyl methylcellulose.
 34. A modulated release pharmaceuticalconstruct which comprises a matrix of a material selected from the groupconsisting of (a) a high melting fatty acid ester, (b) an oil, (c) acellulosic polymer and (d) a mixture of any of the foregoing, and awater insoluble medicament associated with said matrix.
 35. Theconstruct as defined in claim 34 wherein the matrix further comprises asurfactant added to said material.
 36. The construct as defined in claim34 wherein the matrix comprises a mixture of said material (a) through(c).
 37. The construct as defined in claim 34 wherein the matrix isformed from a mixture comprising said ester selected from the groupconsisting of glyceryl behenate, glyceryl palmitostearate and glycerylstearate; said oil selected from the group consisting of corn oil,cottonseed oil, menhaden oil, safflower oil, sesame oil, shark-liveroil, soybean oil, olive oil, wheat grain oil; and a low viscositypolyglycolized glyciride and said polymer selected from the groupconsisting of methocel A series, methocel E series, methocel K series,ethocel P series, a low substituted hydroxypropyl ether cellulosicpolymer selected from the groups consisting of LH11, LH22 and LH30. 38.The construct as defined in claim 37 wherein said mixture furthercomprises a surfactant comprising a non-ionic surfactant.
 39. Theconstruct as defined in claim 34 wherein said water insoluble medicamentis a medicament selected from the group consisting of hydroxyzinepamoate, nifedipine, nimodipine, nisoldipine, nicardipine, amoldipine,atorvastatin, simvastatin and lovastatin, genfibrozil, fenofibrate andclofibrate.
 40. A sustained release pharmaceutical compositioncomprising: a construct comprising a component selected from the groupconsisting of (a) a high melting fatty acid ester, (b) an oil, (c) acellulosic polymer and (d) a mixture of any of the foregoing, and awater insoluble medicament associated with said construct;
 41. Asustained release/prolonged release pharmaceutical unit dosage formcomprising: (a) a hard shell capsule; (b) a carrier construct having amatrix of a material selected from the group consisting of (a) a highmelting fatty acid ester, (b) an oil, (c) a cellulosic polymer and (d) amixture of any of the foregoing, and a water insoluble medicamentassociated with said matrix.
 42. A process for preparing asustained/prolonged release pharmaceutical unit dosage form, whichcomprises: (a) fluidizing a carrier comprising a component selected from(a′) a high melting fatty acid ester, (b′) an oil, (c′) a cellulosicpolymer and (d′) a mixture of any of the foregoing components, to form acarrier solution; (b) adding a water insoluble medicament to saidcarrier solution to form a medicament solution; (c) transferring saidmedicament solution to a hard shell capsule to solidify said medicamentsolution to form the dose having a component matrix with said medicamentassociated therewith.